Acute Respiratory Failure Caused by Leptospira spp. in 5 Foals
Corresponding author: G. van Loon, Department of Large Animal Internal Medicine, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium; e-mail: Gunther.vanLoon@UGent.be.
Although clinical disease in horses is uncommon, serological surveys show that equine exposure to leptospires is very common. In some populations, up to 80% of the animals have leptospiral antibodies.[1, 2] In Europe, Leptospira interrogans serovar bratislava, copenhageni, and patoc are the presumed host-adapted serovars of horses.[3-5]
Clinical leptospirosis in horses is primarily associated with recurrent uveitis, abortions, stillbirth, neonatal disease, hemolysis, renal disease, and liver disease. Unlike cases in humans or small animals, respiratory signs caused by alveolar hemorrhage have not been associated with leptospirosis. The present report describes 5 cases of foals with respiratory distress caused by leptospirosis.
A 3-week-old warmblood filly was presented with icterus and severe respiratory distress. On initial evaluation tachycardia, increased breath sounds, and icteric mucous membranes were found. Laboratory evaluation identified anemia (PCV, 14%; reference range, 28–47%), thrombocytopenia (2 × 109/L; reference range, 100–350 × 109/L), azotemia (urea, 71.4 mmol/L; reference range, 4–9 mmol/L and creatinine, 1,397 μmol/L; reference range, 88–176 μmol/L), and severe acidosis. Thoracic ultrasonography disclosed numerous comet tail artifacts and hypoechoic areas. The foal died shortly after admission and before initiation of treatment.
At necropsy, enteritis and a generalized pneumonia with multiple areas of alveolar hemorrhage were found. Histological examination of the lungs identified multiple sites of pulmonary hemorrhage. Alveoli were filled with red blood cells, hemosiderophages, and some neutrophils, lymphocytes, and plasma cells. Direct immunofluorescence testing identified abundant presence of Leptospira antigen in kidney tissue. Immunofluorescence on liver tissue was mildly positive.
Cases 2 and 3
Two 2-month-old warmblood foals, 1 colt and 1 filly, from the same farm were referred for evaluation of fever and acute respiratory distress. Both foals were lethargic and dyspneic. Increased breath sounds, tracheal rhonchi, high heart rate, and enlarged submandibular lymph nodes were identified on physical examination. Irregular pleura, numerous comet tail artifacts, and some hypoechoic areas were observed on thoracic ultrasonography. Blood was seen in the trachea of the filly on endoscopy. The trachea of the colt was normal. Laboratory examination disclosed anemia (colt, PCV 22%; filly, PCV 26%), thrombocytopenia (colt, 96 × 109/L; filly, 70 × 109/L), and severe azotemia (urea colt, 39.3 mmol/L; urea filly, 46.4 mmol/L and creatinine colt, 875 μmol/L; creatinine filly, 937 μmol/L). Serum of neither foal was hemolytic. The colt additionally suffered from hyperbilirubinemia, mainly caused by an increase in conjugated bilirubin (42.8 μmol/L; reference range, 0.0–8.5 μmol/L).
Both foals were treated with crystalloid fluids, rifampicin1 (7.5 mg/kg, PO, q12h), and clarithromycin2 (7.5 mg/kg, PO, q12h) and were nebulized with clenbuterol3 (0.7–0.8 μg/kg, q8h) for 3 days. Azotemia did not improve, and primary renal failure was suspected. Ultrasound examination of the kidneys disclosed a loss of corticomedullary distinction. Urinalysis showed isosthenuria, pyuria (filly), and hematuria (colt), but no bacteriuria. Renal failure, fever, and hematuria or pyuria, in the absence of bacteriuria, were suggestive for leptospirosis. On day 3, antibiotic treatment was changed to cefquinome4 (1 mg/kg, IV, q12h), and continuous rate infusion of furosemide5 (0.25–2.0 mg/kg/h) was started.
Serologic microscopic agglutination tests (MAT) indicated high L. interrogans serogroup australis serovar bratislava titers in both foals (both 1 : 2,000) and their dams (1 : 2,000; 1 : 1,000), with cross reactions to other serovars in the colt and its dam. The colt also had high antibody titers to serovars of the serogroup grippotyphosa (1 : 2,000).
Because of worsening dyspnea and increasing azotemia, the colt was euthanized after 5 days. Necropsy identified icterus; multifocal petechiae in the kidneys, lungs, and liver; interstitial pneumonia with emphysema and focal hemorrhages; and interstitial nephritis and glomerulonephritis. Direct immunofluorescence antigen detection in kidneys and liver confirmed the diagnosis of leptospirosis.
The filly received cefquinome4 and continuous rate infusions of glucose6 (6 mg/kg/h) and dopamine7 (1–10 μg/kg/h) for 10 days and furosemide5 for 5 days. The filly completely recovered and was discharged after 17 days of hospitalization. One month later, serum antibody titers in the filly and the mares had decreased markedly (<1 : 100).
A 2-month-old warmblood filly was presented with complaints of lethargy and respiratory distress. Clinical examination identified icteric mucous membranes, severe respiratory distress, tachycardia, and a temperature of 38.7°C. Thoracic ultrasound examination identified comet tail artifacts and several large consolidated areas within the pulmonary parenchyma, but no abscesses. Anemia (PCV 24%), thrombocytopenia (32 × 109/L), leukocytosis (86.2 × 109/L; reference range, 4–9 × 109/L), azotemia (urea, 61,9 mmol/L; creatinine, 1,255 μmol/L), and hyperbilirubinemia, with marked increase in conjugated bilirubin (121.4 μmol/L), were found on laboratory evaluation. Treatment was declined by the owner, and the foal was euthanized.
Necropsy identified generalized icterus; multiple petechiae in the spleen, kidneys, lungs, intestines, and heart; glomerulonephritis, and interstitial pneumonia. On histopathology, multiple hemorrhagic areas were present in the lungs with multifocal infiltration of lymphocytes, plasma cells, and hemosiderophages. Direct immunofluorescence antigen detection in kidneys and liver confirmed the presence of Leptospira.
A 5-month-old colt was referred for evaluation of respiratory distress and hemoptysis. Severe respiratory distress, fever, and tachycardia were present on clinical examination. Pulmonary ultrasound examination showed numerous comet tails and large consolidated areas. Mild azotemia (urea, 13.9 mmol/L; creatinine, 221 μmol/L) was present on laboratory evaluation.
The foal was treated with rifampicin1 (7.5 mg/kg, PO, q12h), clarithromycin2 (7.5 mg/kg, PO, q12h), and continuous rate infusion of glucose (6 mg/kg/h) and was nebulized with clenbuterol3 (0.7–0.8 μg/kg, q8h). Within a few hours, its general condition deteriorated and the colt was euthanized.
Necrotic interstitial pneumonia with bronchial lymphadenitis and extensive pulmonary hemorrhages were present at necropsy. Alveolar necrosis with intra-alveolar edema, fibrin deposits, and infiltration of macrophages and hemosiderophages were observed on histopathology. Leptospirosis was confirmed by direct immunofluorescence antigen detection in kidneys and liver.
Although respiratory manifestations have been described in 20–85% of human patients with clinical leptospirosis, the disease mostly is associated with jaundice and renal failure.[6-8] Over the last 2 decades, an increasing number of cases in different geographic areas have been characterized predominantly by pulmonary hemorrhage.[8, 9] In recent studies of human patients, thoracic radiographs were found to be abnormal in 25–65% of cases, and intra-alveolar hemorrhage was detected in the majority of patients, even in the absence of overt pulmonary symptoms.[8, 10] The mortality of this severe pulmonary hemorrhage syndrome caused by Leptospira spp. is high (over 50%), even when optimal treatment is provided. Why more patients with leptospiral infection have been developing respiratory complications remains unknown. An unknown interaction with a respiratory virus or a variation in leptospiral strain has been hypothesized.
Clinical and radiographic evidence of lung disease also has been reported in dogs with leptospirosis.[11-13] In a report by Kohn et al, more than 70% of 50 dogs with leptospirosis suffered from pulmonary complications in addition to renal and hepatic failure, and 43% of them were euthanized.
Pulmonary hemorrhage because of leptospirosis in horses has been reported rarely, but respiratory problems often are mentioned in case reports. Especially in foals with leptospiral infection, respiratory signs, pulmonary changes on necropsy, or both have been reported.[14-16] Although no age predilection has been reported in human and canine cases, all affected horses in this case report were younger than 6 months.
Severe respiratory distress was the most prominent clinical sign in these foals, in addition to the more common clinical signs of leptospirosis, such as kidney failure and icterus. On thoracic ultrasound examination, all foals showed increased comet tail artifacts and hypoechoic areas because of consolidation or hemorrhage. Pulmonary hemorrhage and interstitial pneumonia with infiltration of red blood cells, hemosiderophages, and neutrophils were observed at necropsy. These pathological findings are similar to those found in human and canine cases of pulmonary leptospirosis. As in humans and dogs with severe respiratory distress associated with leptospirosis, mortality rate was very high (80%).
In the cases of this report, the diagnosis of leptospirosis was primarily based on results of direct immunofluorescence antigen detection in kidney and liver tissue. Unfortunately, antigen detection in pulmonary tissue was not performed in any of the cases. In studies of affected humans however, immunofluorescence did reveal leptospiral antigen in pulmonary tissue, suggesting that the microorganism exerts a local direct destructive action. Immunofluorescence on lung tissue thus might be useful to diagnose pulmonary leptospirosis.[6, 8]
Serology (MAT) was performed in cases 2 and 3. The high antibody titers against Leptospira spp. at admission, and the marked decrease 1 month later, further support the diagnosis of leptospirosis.
Little is known about the pathogenesis of pulmonary hemorrhage in cases of leptospirosis. Leptospira spp. commonly are assumed to cause tissue damage by means of systemic vasculitis. Some recent studies, however, suggest that tissue damage results from primary damage to parenchymal cells or from direct endothelial damage with increased vascular permeability. Several studies showed endothelial damage in lung tissue and fibrin deposits in the alveolar walls as a constant and uniform feature.[9, 17] A recent experiment reproducing alveolar damage caused by leptospirosis in the hamster showed that the progression of lung lesions paralleled the expression of tumor necrosis factor and endothelial nitric oxide synthase. These data suggest a role of local or systemic inflammation or both in the pathogenesis.[8, 9, 18] On the other hand, an immunologically mediated mechanism of pulmonary hemorrhage also has been proposed.[9, 19] Using a guinea pig model, Nally et al reported deposition of immunoglobulin and complement along the septal surfactant. The hypothesis of an immunologically mediated mechanism however was challenged by the recent description of lethal disease with pulmonary hemorrhage in experimentally infected mice with severe combined immunodeficiency. These data suggest that the pathogenesis of pulmonary hemorrhage probably is multifactorial, and many of the associated factors are poorly understood.
Thrombocytopenia is a frequent feature of leptospirosis. In this case report, 4 of 5 foals suffered from thrombocytopenia. In humans, it is currently unclear whether disseminated intravascular coagulation is an important feature of leptospirosis, although recent data suggest that only a small fraction of patients develop activation of the coagulation pathway and fibrinolysis.[7, 8] Furthermore, the genome of L. interrogans harbors some genes coding for proteins that are thought to be involved in the disruption of hemostasis, such as platelet activating factor, acetylhydrolase, and a protein similar to domain A of Von Willebrand Factor.
A better understanding of the pathogenesis is important in the search for evidence-based treatments for respiratory complications of leptospirosis. Until now, a variety of different antibacterial and symptomatic treatments, including anti-inflammatory drugs and corticosteroids, have been reported. Recently, some research has been done on the effects of immunosuppressive drugs to treat immune-mediated pulmonary damage. The use of glucocorticoids in an early phase had a positive effect in several studies,[21, 22] although results of other studies contradict this effect. Trivedi et al obtained good results by using cyclophosphamide to treat hemorrhages caused by leptospirosis in humans. Because the diagnosis of leptospirosis was not immediately evident in the foals in this report, they were treated with broad spectrum antibiotics and received additional circulatory and nutritional support.
In human medicine, jaundice and renal failure are the most frequently reported presentations of leptospirosis. Over the last decades, however, more patients have suffered from acute respiratory distress because of massive alveolar hemorrhage caused by Leptospira spp. Pulmonary hemorrhage is now considered the most important cause of death in human patients with leptospirosis. Also in dogs, some recent reports indicate the growing importance of a pulmonary component in leptospirosis. Until now in equine medicine, leptospirosis has mostly been linked with renal and hepatic failure. This case report shows that respiratory signs associated with interstitial inflammation, alveolar damage, and hemorrhage because of leptospirosis do occur in foals. Leptospirosis should therefore be included in the differential diagnosis of acute respiratory distress in the foal.
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